Sophie Deram 2

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129Arq Bras Endocrinol Metab. 2009;53/2

Genetic variants influencingeffectiveness of weight loss strategies

Variantes genticos influenciando a efetividade

das estratgias de perda de peso

Sophie Deram1,2, Sandra M. F. Villares1,2

ABSTRACT

Body weight excess has an increasingly high prevalence in the world. Obesity is a complexdisease of multifactorial origin with a polygenic condition affected by environmental factors.Weight loss is a primary strategy to treat obesity and its morbidities. Weight changes throughlife depend on the interaction of environmental, behavioral and genetic factors. Interindividualvariation of weight loss in response to different types of interventions (behavioral, caloric res-triction, exercise, drug or surgery) has been observed. In this article, currently available dataon the role of candidate gene polymorphisms in weight loss are reviewed. Even though controlof weight loss by genotype was described in twin and family studies, it is premature to recom-mend use of genotyping in the design of therapeutic diets or drug treatment. Future studieswill have to be large in order to assess the effects of multiple polymorphisms, and will have tocontrol factors other than diet.Arq Bras Endocrinol Metab. 2009;53(2):129-138.

Keywords

Polymorphisms, genetic; gene variant; weight loss; obesity

RESUMO

A prevalncia do excesso de peso cresce no mundo todo. De origem multifatorial, a obesidade

uma doena complexa, com condio polignica afetada por fatores ambientais. A perda de peso a estratgia primria utilizada para prevenir e tratar a obesidade bem como suas comorbidades.Mudanas de peso durante a vida dependem da interao entre fatores ambientais, comporta-mentais e genticos. Observa-se grande variao da perda de peso entre indivduos em respostaa diferentes modelos de intervenes (comportamentais, restries da ingesta clorica, exercciosfsicos, drogas antiobesidade ou cirurgias). Este artigo uma reviso atual da literatura disponvel,que busca abordar o papel dos polimorfismos dos genes candidatos obesidade e sua influnciana perda de peso. Apesar da interao do gentipo na perda de peso corporal, descrita nos estu-dos de gmeos e familiares, prematuro recomendar o uso da genotipagem para estratgias deperda de peso. necessrio ampliar as pesquisas sobre os efeitos sinrgicos dos polimorfismosgenticos com coorte maior e associ-los no somente restrio alimentar mas tambm s ou-tras intervenes que auxiliam na perda de peso. Arq Bras Endocrinol Metab. 2009;53(2):129-138.

Descritores

Polimorfismo, gentico; diversidade gentica; perda de peso; obesidade

1 Laboratrio de Nutrio

Humana e Doenas Metablicas

(LIM-25), Faculdade de Medicina

da Universidade de So Paulo(FMUSP), So Paulo, SP, Brasil2 Ambulatrio de Obesidade

Infantil, Hospital das Clnicas

da Faculdade de Medicina da

Universidade de So Paulo

(HC-FMUSP), So Paulo, SP, Brasil

Correspondence to:

Sophie Deram

Laboratrio de Nutrio Humana

e Doenas Metablicas LIM-25,

HC-FMUSP

Av. Dr. Arnaldo, 455, sala 4305

01246-903 So Paulo, SP, Brasil

[email protected]

Received in Feb/12/2009

Accepted in Feb/15/2009

INTRODUCTION

Excess body weight is highly prevalent in most coun-tries and the rapid weight gain in the populationis likely due to a changing environment (obesogenic

environment and behavior), with a misbalance between

energy consumption and energy expenditure and in-

dividual genetic sensibility to weight gain. Numerous

epidemiological studies have reported that an excess

of body weight is associated with a higher risk of de-

veloping a number of chronic diseases, such as type 2

diabetes, cardiovascular disease and increased incidence

of certain forms of cancer. Treatment or prevention of

obesity is advised to reverse or avoid the onset of type

2 diabetes and other obesity-related diseases, and the


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130 Arq Bras Endocrinol Metab. 2009;53/2

current management of obesity is directed primarily to

reduce energy intake and increase energy expenditure.

Regulation of body weight and energy homeostasis is

subject to complex regulatory mechanisms maintaining

balance between energy intake, energy expenditure and

energy stores.There are a number of strategies that can be used to

induce negative energy balance and weight loss, such

as lifestyle modification including a reduction of en-

ergy intake, an increase in physical activity, a behavioral

approach, and pharmacological or surgical treatment.

Those strategies may result in significant weight loss

in obese subjects, however the individual response is

very variable. Existence of hypo or hyper responders

supports the hypothesis that response to weight loss

intervention is related to genetic variation and reliable

predictors of successful weight loss are still not well un-derstood. Weight loss is a complex trait that depends

on many environmental, behavioral and genetic influ-

ences. The gene-environment interaction explains why

some individuals are more prone to weight gain than

others in a similar environment.

Genetic factors play an important role in weight

regulation, since there are genes involved in regulation

of energy expenditure, appetite, lipid metabolism, adi-

pogenesis, thermogenesis, cell differentiation.

Association and linkage studies indicate links be-

tween candidate obesity genes and body weight, bodymass index (BMI), body fat, fat distribution, energy

expenditure, fuel oxidation and several other pheno-

typic characteristics of obesity, including obesity related

health risks. More than 600 genes and chromosomal re-

gions have been reported to participate in body weight

and energy metabolism regulation. Genes that have

been associated or linked to human obesity are nume-

rous, whereas gene-environment interaction in relation

to weight change has been studied less frequently.

The strong control of weight loss by genotype was

confirmed by studies conducted in monozygotic twins(1). In addition to these, there are studies performed

in unrelated subjects evaluating the effect of known ge-

netic polymorphisms on weight loss response after dif-

ferent types of interventions. One must not forget that

the candidate genes variants that are associated with

weight loss in obese people are often the same variants

that were previously associated with obesity and weight

gain. These associations among genetic groups might

be confounded by differences in baseline measurements

of obesity-related variables.

Most studies have focused on weight loss after a single

intervention in a relatively homogeneous group where a sin-

gle or multiple genes were associated and where weight loss

was not the primary focus of the study. A few studies were

performed where weight loss intervention was primarily car-

ried out in different genotype groups matched by relevantobesity-related variables. Some studies also consisted in con-

trolled intervention trials with different treatment applied to

two or more randomized groups, in which weight loss per

genotype was not again the primary aim.

These studies relating weight loss interventions are

difficult to compare and interpret because they show

very heterogeneous populations (men, women, chil-

dren, obese, overweight, diabetic or pre-diabetic),

heterogeneity in the duration and type of treatment

(dietary, pharmacological, surgery), difference in the

sample size, lack of adequate control groups, contra-dictory apparent results, difficult to replicate and some

possible non-publication of negative results.

Moreover, some groups reported synergetic effects

of polymorphisms from different loci in the ability or

resistance to weight loss therapies. All these interactions

increase the complexity of prediction of a response to

weight loss with genetic tests approach.

The purpose of this study was to provide an extensive

overlook of current evidence, through literature review

(2,3) on the role of the genetics on weight loss. This

review for time and resource limitation is not an exten-sive and systematic review. We studied the most plau-

sible candidate genes that are involved in energy balance

pathways, body composition changes in response to diet

or exercise interventions. We restricted our article to

weight loss in excess weight population and didnt focus

on weight loss maintenance and weight regain.

A summary of the genes candidates to influencing

weight loss in weight loss strategies can be retrieve in

Table 1.

GENES RELATED TO ENERGY EXPENDITURE

Genes encoding proteins that are key regulators of

energy balance are likely involved in modulation of

body weight response to environmental changes. The

change/adaptation of the metabolic rate after weight

loss (reduction of fat-free mass) is described as being

very variable with individuals: some will decrease and

adapt to the new body size, others will decrease more

and resist to weight loss. This inter-individual difference

suggests genetic make-up effect.

Gene variants and effect on weight loss


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Adrenergic receptor genes

Adrenergic receptor genes (ADRB) play an important

role in the adipocyte metabolism, mediating the rate of

catecholamine-induced lipolysis. The adrenergic system

plays a key role in regulating energy balance through

thermogenesis and lipid metabolism.For the ADRB3 Trp64Arg polymorphism (the most

described), carriers of the Arg64 are more resistant to

weight loss for homozygotes (4) or women carrying

the allele (5). Other studies did not confirm this as-

sociation with weight loss studying various ADRB3

polymorphisms (6,7), nevertheless a resistance to loose

visceral fat was described in carriers of Arg64 confirmed

by Nakamura and cols. (8). On the other hand, in 2001,

Xinli and cols. described a better weight loss in children

carriers of Arg64 (9).

An interesting study on Japanese women who com-pleted 12-week lifestyle intervention linked the pres-

ence of 64Arg allele to resistance to weight loss, but

this association disappeared after adjusting for the per-

centage change of energy intake (10).

Synergies between ADRB3 (Trp64Arg) and insulin

receptor substrate IRS-1 (Gly972Arg), polymorphisms

were described as resistant to weight loss for carriers of

both less common alleles (11) in obese women after 13

week intervention.

Synergies between ADRB3 and UCP1 were de-

scribed with a lower loss of weight when both polymor-

phisms were present (12,13). In 2004, Kim and cols.

(14) studied synergies between ADRB3 and UCP3 on

224 overweight-obese subjects who underwent a 12-

week mild weight reduction program (-300 kcal/day)

and separated them in four categories per genotype of

ADRB3and UCP3. Despite similar weight reduction,

they observed a higher abdominal adipose reduction in

the wild type group and linked the presence of both

variants to lower reduction. They observed on a bene-

ficial effect of the weight loss program on wild type and

that carriers of variant of ADRB3 were less beneficial.

ADRB2s polymorphisms were most studied in

weight loss maintenance and regain after two years,

with a description of the Gly16 carriers being less able

to maintain weight loss (15).

Uncoupling proteins

The uncoupling proteins (UCPs) are a family of car-

rier proteins located in the inner mitochondrial mem-

brane. Playing an important role in energy metabolism

in cells, UCP polymorphisms were described as influ-

encing exercise efficiency, resting energy expenditure,

substrate oxidation, energy metabolism, body weight

change etc.

UCP-1 (A3826G) polymorphism was linked to

lower weight loss response to a 25% reduction of ener-

gy intake (6). This group found that GG homozygoteswere more resistant to weight loss. In Korean women,

haplotypes of UCP1ht3(GAG) was found to be linked

to higher weight loss after one month of very low calo-

rie diet (VLCD) intervention (16).

A recent study showed associations with weight

loss after VLCD and haplotypes of ten polymorphisms

(four of UCP2and six of UCP3) (17) and concluded

that UCP2-3polymorphisms were good predictors of

reduced body fat in response to VLCD.

GENES AND CONTROL OF APPETITE

The regulation of food intake involves several genes

and the mechanisms are coming clearer. Lately, much

attention has been focused on the role of the hypotha-

lamic leptin-melanocortin system.

Leptin

Lower weight loss was described for the leptin (LEP)

gene polymorphism in the promoter region 5 (18)

and for the carriers of the -2549A allele at position

C-2549A, after low-calorie diet in obese women.

Leptin receptor

Two studies linked effect of polymorphism of leptin

receptor (LERP) and weight loss: overweight women

carrying the C allele of the Ser (T) 343 Ser (C) poly-

morphism lost more weight after low calorie diet than

non-carriers (19), and the Lys656Asn was shown not

to have influence in weight loss (20).

Melanocortin system genes

Proopiomelanocortin (POMC) polymorphism R236G,

even though linked with early onset obesity, showed no

influence on the ability to loose weight in three chil-

dren heterozygous (21).

Mutations on MC4R, associated with intense feel-

ing of hunger and hyperphagia in childhood that de-

crease with aging, were described as not impacting abil-

ity to loose weight with a study evaluating influence on

weight loss (22).



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A clear gene-diet interaction between MC3R

Thr6Lys and Val118Ile was recently described in the

ability to lose weight (23) in obese children.

Serotonin receptor HTR

Serotonin is involved in food intake regulation in the

central nervous system (CNS). Heterozygous at the

HTR2C(C759T) promoter is linked to more resistance

to weight loss than homozygous CC or TT after weight

loss program; some studies concluded that heterozy-

gosity impairs the ability to lose weight (24).

Neuromedin beta

Neuromedin beta (NMB) is a member of the bombe-

sin-like peptide family expressed in brain, gastrointes-tinal tract, pancreas, adrenals and adipose tissue. The

polymorphism (Pro73Thr) has been linked to higher

disinhibition and more hunger and greater body fat

accumulation, and was described as influent on the

change in fat mass in the Qubec Family Study (QFS).

Recently, a study linked male T allele carriers of the

(P73T) polymorphism to resistance to weight loss, but

not in women (25).

ADIPOGENIC GENESPeroxisome proliferator-activated receptor (PPAR)

These genes are involved in regulation of adipocyte

growth and differentiation and were already associated

with body weight control (26).

PPARG2 is a key transcription factor implicated

in adipogenesis, glucose and lipid homeostasis. The

polymorphism Pro12Ala was already linked positively

to BMI and subjects with impaired glucose tolerance.

Homozygotes for Ala12 allele were more successful in

losing weight (27) in a three-year study and success inweight maintenance (28). Finally, a recent study (29)

observed that this polymorphism was associated in

obese women with diet resistance even after correction

for baseline BMI.

However, others studies (30) described no differences

in weight loss for carriers of Ala12: a study of postmeno-

pausal obese women after six months of hypocaloric diet

(they had a higher weight regain after 12 months follow-

up), another (31) in obese patients in a four-year period

and also in obese with type 2 diabetes (32).

An interesting finding is that diet and exercise have

opposite effects on weight loss in Ala12 carriers: they

appear more resistant to diet-induced weight loss but

more prone to loss on standard exercise training inter-

vention (33).

GENES OF THE LIPID METABOLISM

Apolipoproteins

Kee and cols.(34) showed that subjects carrying variant

of the Apolipoprotein E (apoE) e4 are more resistant

to weight loss.

Apolipoprotein A (apoA-IV) was described to be in-

volved in the regulation of food intake and a study eval-

uating effect of polymorphism (T-1131C) on weight

loss showed that C carriers are more prone to loose

weight (35). On the other hand, another study (36)found no difference in weight loss.

Apolipoprotein A5 (ApoA5) plays a role in triglycer-

ides metabolism, and the T-1131C polymorphism was

found to be associated with weight loss after short-term

dietary restriction in hyperlipaemic overweight men

(37) with C carriers showing a higher BMI reduction,

factor that was confirmed in another study, in which C

carriers lost significantly more weight (38).

Hepatic lipase gene (LIPC)Subjects with the G-250A promoter polymorphism

showed difference in weight loss, both in control and

intervention groups (39).

Perilipins

Perilipins (PLIN) are a family of proteins that coat

the intracellular lipid droplet. They are key regulators

of the lipolysis and triglycerides mobilization. Poly-

morphism (G11482A) was described as influencing

weight loss during body weight reduction strategy oflow-energy diet; obese patients carrying 11482A al-

lele were more resistant to weight loss after one year

(40). This finding was not confirmed in obese chil-

dren after 20-week lifestyle intervention, although the

metabolic syndrome risk was very high among carrier

of 11482A allele. Interestingly, another PLIN SNP

(A14995T) was associated with better weight loss re-

sponse to the intervention (41). The best response to

weight loss was linked to homozygotes of G11482

and 14995T alleles.



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Acyl CoA synthetase 5 (ACSL5)

These ACSL genes catalyze the production of fatty

acyl-CoAs, and a SNP rs2419621 (C/T) was linked to

weight loss response to diet in obese women (29).

GENES OF THE INSULIN PATHWAY

No significant weight reduction was described to geno-

type in the Finnish Diabetes Prevention Study (DPS), a

large study that observed the influence on several vari-

ants of genes related to insulin signaling pathway: insu-

lin gene, insulin-like growth factor 1 receptor (IGF1-

1R), insulin receptor substrate 1 and 2 (IRS-1and 2)

and more on a lifestyle intervention on overweight sub-

jects with impaired glucose tolerance (42). However,

they suggested that lifestyle intervention was not suc-

cessful in subjects carrying IGF-1R, IRS-1 and IRS-2polymorphisms.

Another study described an influence on weight loss

when analyzing synergies between carriers of the IRS-1

(Gly972Arg) polymorphism and ADRB3 (11).

Recently, a study confirmed that children homozy-

gous CC for the SNP rs7566605 (10kb from the insu-

lin gene 2 (INSIG2)) are more resistant to weight loss

after one-year lifestyle intervention (43).

OTHER GENES RELATED TO OBESITYIn 2004, Tworoger and cols. (44)studied two genes

and their synergies on weight loss after exercise in-

tervention: subclass 19 cytochrome P450 aromatase

(CYP19) and catechol-O-methyl-transferase (COMT).

CYP19contains a tetranucleotide repeat polymor-

phism (TTTA), from which 11r allele was associated

with a higher loss of BMI and total fat after exercise-

induced in post-menopausal women intervention. A

smaller weight loss was observed in carriers of Met/

Met versus Val/Val genotype of COMT. The best

weight loss was linked to carriers of CYP19 11r andCOMT (Val/Val).

The plasma factor VII (Arg-Gln353) gene polymorphism

was not linked with ability to loose weight in a six-month in-

tervention in moderately obese men and women (45).

The angiotensin-converting enzyme insertion-

deletion (ACE I/D) polymorphisms were not linked

to weight loss on 86 elderly white overweight hyper-

tensive subjects, but DD carriers showed a significant

decrease in blood pressure and therefore weight loss

sensitivity (46).

Some very recent strong positive associations with

genes like FTO and obesity were reported. A recent

study did not observed influence on weight loss for the

polymorphism (rs9939609) on intervention program

for German obese children and adolescents (47).

GENES AFFECTING RESPONSE TO DRUG

TREATMENT OF OBESITY

Studies on drug induced weight loss provide addi-

tional evidence that genotyping could be of relevance

in predicting efficacy of antiobesity drugs for obesity

treatment.

Sibutramine

Sibutramine, a promising drug for treatment of obesity,inhibits noradrenaline and serotonin reuptake and also

enhances satiety. However a very large variety of weight

loss response has been described.

Serotonin transporter is encoded by the gene sol-

ute carrier family 6 (neurotransmitter transporter, sero-

tonin), member 4 (SLC6A4) with long(L) and short(S)

alleles.

There is a higher risk of adolescent obesity in S car-

riers (48) and LS/SS genotype was associated with bet-

ter weight loss after treatment (49).

The Guanine nucleotide-binding protein (G-pro-

tein), beta-3 subunit (GNB3) polymorphism C825T

was linked to difference in weight loss between control

group and group with sibutramine (50) with a higher

weight loss on carrier of T allele in the control group

and a higher weight loss for the CC homozygotes when

treated with Sibutramine.

Phenylethanolamine N-methyltransferase (PNMT)

is an enzyme that acts in catecholamine metabolism and

catalyses the conversion of norepinephrine to epineph-

rine. Obese women AA carriers of (G148A) had a bet-ter weight loss after 3-month therapy (51) but not after

6 months.

A recent study (52) evaluated overall weight loss ef-

fect of placebo vs. sibutramine treatment for 12 weeks

on 181 overweight or obese individuals and linked sig-

nificant response to weight loss for the 2Aadrenore-

ceptor C1291G, 5-HTTLPR, and GN3C825T geno-

types. With an enhanced effect with both 5-HTTLPR

LS/SS and GN3 TC/TT, as well as2A CC with

GN3TC/TT.



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Mazindol

ADRB3 carriers of the polymorphism (Trp64Arg)

showed a resistance to weight loss (53) when treated

with mazindol.

GENES INFLUENCING RESPONSE TO BARIATRIC

SURGERY

Interleukin 6 (IL6) and UCP2 genes were linked to

weight loss after laparoscopic gastric banding after six-

months follow-up (54). Carriers of the C allele of IL6

G-174C polymorphism and carriers of the G allele of

UCP2 G-866A were more resistant to loose weight.

Several polymorphism of UCP2 gene were studied

and rs660339 (Ala55Val) was linked to greater weight

loss after 12 and 24 months for morbidly obese patientswho underwent laparoscopic adjustable gastric band-

ing, but this was not observed in the ones who under-

went laparoscopic mini-gastric by-pass (55).

UCP-1polymorphisms A-3826G was not linked to

weight loss after gastroplasty on morbidly obese sub-

jects (56) after three-year follow-up.

None of the G protein (GNB3,C825T, G814A and

GNAS1T393C) polymorphisms were linked to weight

loss in a population of 304 obese people, who under-

went bariatric surgery (57).

COMPREHENSIVE MULTI GENE STUDIES

Some comprehensive studies on gene-nutrient inter-

action have been managed by the Nutrient-Gene In-

teractions in Human Obesity: Implications for Dietary

Guidelines (Nugenob), some are about SNPs others

about gene expression.

In 2006, Srensen and cols. (58), in a study about

weight loss, concentrated results from eight clinical

centers in Europe (648 obese adults), about 26 obesity

candidate genes and 42 SNPs in a ten-week weight lossintervention with low-fat or high-fat diets. The authors

did not conclude on any major influence of one par-

ticular SNP.

They studied the most frequent genes involved in

energy balance regulation and suggested a possible

modulation on weight loss of the following genes: pro-

hormone convertase subtilisin/kexin type 1 (PCSK1),

WW domain containing adaptor with coiled-coil

(WAC), 11-beta hydroxysteroid dehydrogenase type 1

(HSD11B1), and tumor necrosis factor-alfa (TNFA)

and also possible link with haplotypes of the glutamic

acid decarboxylase 2 (GAD2) and ectonucleotide py-

rophosphatase/phosphodiesterase 1 (ENPP1). The

conclusion was that possibly more severe diet restric-

tion and more duration are required to reveal a possible

gene-diet interaction in weight loss intervention.In 2006, Ruao and cols. (59) described a sig-

nificant association with some genes and weight loss

during a 4 to 12-week low carbohydrate intervention

(CHO 10% of the total energy intake) on 86 normal

and overweight healthy adults. Genotyping of 27 SNPs

were studied and four had statistically significant associ-

ation with weight loss: gastric lipase (LIPF, rs814628),

hepatic glycogen synthase (GYS2) (rs2306179), cho-

lesteryl ester transfer protein (CETP) (rs5883) and

galanin (GAL, rs694066).

CONCLUSION

This review summarizes the current findings on selec-

ted genes candidates and their possible role in influen-

cing weight loss in weight loss strategies. The weight

loss response to dietary change or to strategies such as

exercise, drugs or surgery, is highly complex and with

large interindividual variability. The healthy state and

prevention of excess weight should have more atten-

tion than the bathroom scale.

The real challenge during weight loss is the loss offat mass, and it is unfortunately accompanied with loss

of lean mass; another challenge is a good maintenance

of weight loss. Failure to recognize the benefits of exer-

cise independent of weight loss masks opportunities to

counsel and educate patients.

The variability of the response to intervention in

the numerous interventional studies shows a lack of

homogeneous data in order to be able to compare

them: ethnicity, physical condition, age, lifestyle differ-

ences all are characteristics that combined with length

of intervention, sample size make the replication of thestudies published difficult. Caution is needed before

applying these results to clinical practice. Future studies

will have to be large in order to assess the effects of

multiple polymorphisms, and will have to control for

many factors other than diet.

We reported various contradicting results; for ex-

ample, in the children population, the results after

weight loss intervention are not similar to those ob-

served in adult population (41) they are even contra-

dictory (9).



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This biais could be explained by a different meta-

bolic adaptation to excess weight in young obese, that

are not yet in state of resistance to weight loss, but will

develop it later in life.

We also reported that losing weight may be more

effective for some genotypes than others; furthermore,interventions for weight loss with no apparent effect on

weight will have a positive effect on weight will have a

benefic effect on metabolic status and were shown to

reduce cardiovascular risk factors (36,46). Some indivi-

duals will also be hyper responder to weight loss, but will

not maintain the weight and, sometimes, the presence of

hetrozygosity may impair the weight loss success (24).

More and more, the synergies in between genes are

being studied and multiple positive genotypes can

act synergically (44).

Finally, lifestyle factors, such as decrease in energyintake, might mask effect on weight loss (10).

We are still at the beginning of the nutrigenetics stu-

dies and this is not enough to start specific personalized

nutritional recommendations based on genetic infor-

mation (60). At present, it is premature to recommend

the use of genotyping in the design of therapeutic diets

or drug treatment. However, such studies are very use-

ful in identifying the mechanisms by which individuals

are successful in losing weight, maintain it and which

treatment is the more appropriate. Studies on drug-

induced weight loss provide additional evidence that

genotyping could be of relevance in predicting efficacy

of anti-obesity drugs for obesity treatment.

It is possible that more severe energy restriction and

more prolonged weight management program are re-

quired to reveal the role played by gene-diet interaction

in weight loss programs.

And, a question is raised up about the relation be-

tween excess weight and poorer healthy state, since a

significant portion of obese individuals can achieve lon-

gevity without developing the morbidities associated toobesity. One hypothesis is that total body fat is not the

sole source of health complications but the fat distri-

bution is more the determining metabolic risk of the

individual. How healthy is it to lose weight for an indi-

vidual? Is losing too much weight, in a short period of

time, health beneficial and more beneficial than losing

gradually and maintaining weight loss? What is the toll

of yo-yo weight loss on health?

Disclosure: No potential conflict of interest relevant to this articlewas reported.

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